This invention provides methods and compositions useful for the prevention and/or treatment of neurodegenerative and proliferative diseases. The compositions of the invention promote neuronal cell maturation and retard their proliferation. In particular, this invention relates to nonprotein neurotrophic molecules capable of passing the blood brain barrier to provide therapeutic effects.
Proper function of the nervous system requires the maturation and maintenance of neuronal cells. In addition, the establishment of proper synaptic connections allows for the communication between different neurons. Defects in the survival of neurons, or the ability to maintain synaptic connections is associated with neurodegenerative disorders including Alzheimer""s disease, Huntington""s disease, amyotrophic lateral sclerosis (ALS), Parkinson""s disease, stroke and degeneration of neurons due to diabetic neuropathy and trauma.
Many of the neurodegenerative disorders are associated with the loss or degeneration of a particular class of neuronal cells. For example, in Parkinson""s disease dopaminergic neurons of the substantia nigra degenerate. Whereas ALS is associated with the loss of motor neurons. Wernicke-Korsakoff syndrome, commonly associated with chronic alcoholism, causes amnesia due to damage to the mammillary bodies and medial dorsal nucleus of the thalamus. Butters N., Seminar Neurol. (1984) 4:226-244. Alzheimer""s disease appears to be associated with the degeneration of certain cholinergic neurons. The severance of axons as a result of trauma may cause retrograde degeneration and neuronal death.
The association between neurodegeneration and the development of disease has prompted the search for neurotrophic agents capable of retarding, preventing, or reversing such neurodegeneration. To date, much emphasis in this area has focused on the identification and characterization of neurotrophic polypeptides. For example, attention has been given to studying the effects of nerve growth factor (NFG), ciliary neurotrophic factor (CNTF), brain drive neurotrophic factor (BDNF) and others. The general neurotrophic effect of CNTF and, in particular, its trophic action on motor neurons has led to its investigation as a useful agent in the treatment of ALS and other neurodegenerative disorders. See, for example, Collins et al. U.S. Pat. No. 5,141,856 and Masiakowski WO 91/04316 which are incorporated herein by reference. NGF which has been shown to promote neuronal outgrowth from central cholinergic neurons has been suggested as a useful agent in the treatment of Alzheimer""s disease. Most of the neurotrophic polypeptides identified to date are active on relatively restricted populations of neuronal cells. Whereas others such as CNTF are active on a greater number of neuronal cell types.
It has generally been observed that agents which induce maturation or differentiation of neuronal cells in culture, also inhibit their proliferation. Normal proliferating embryonic precursors to sympathetic and sensory neurons are induced to mature and stop dividing in the presence of certain growth factors such as NGF. The association between neuronal maturation or differentiation and anti-mitotic action has also been observed for certain neoplastic cells which are responsive to neurotrophic factors. For example, rat pheochromocytoma, PC12, cells in the presence of NGF develop long neurites and stop dividing. Green LA and Tischler AS, Proc. Natl. Acad. Sci. USA (1976) 72:2424-2428. Similar effects have been observed with other neuronal cells.
Cells in the nervous system give rise to a variety of potentially fatal neoplastic diseases. For example, neuroblastoma and pheochromocytoma are believed to arise from cells having an origin in the neural crest. Non-neuronal cells of the nervous system including glial cells, astrocytes and Schwann cells also give rise to different types of tumors. Most present agents used for chemotherapy involving neuronal cells are cytotoxic and have relatively poor specificity and penetrability. Treatment of neoplastic disease through agents causing maturation has been a long sought for goal. Aaronson, S. A. Science (1991) 254:1146-1153.
Although neurotrophic polypeptides may eventually prove useful for treating certain neurodegenerative, and proliferative disorders, they are characterized by poor bio-availability resulting from their relatively large size making them resistant to passing through the blood brain barrier. This poor penetration into the relevant target tissue raises substantial difficulties in their use for treating neurodegenerative disorders and neoplastic disease of the central nervous system.
The anticonvulsant sodium valproate (VPA) is a branched chain carboxylic acid effective in the treatment of primary generalized seizures, especially those of the absence type. Pinder, R. M. et al., Drugs (1977) 13:81-12. Recently, VPA has been reported to be a teratogen and has been suggested as potentially causing neural tube defects in 1% to 2% of exposed fetuses (Robert E. and Rosa F. W., xe2x80x9cMaternal valproic acid and neural tube defects,xe2x80x9d Lancet (1982) 2:937). In addition, a number of other defects are also induced by valproic acid treatment during pregnancy (Nau et al. J. Pharmacol. Exp. Ther. (1981) 219:768-777. Spina bifida aperta, a most serious birth defect, can now also be induced by valproic acid in an animal model (Ehlers et al., 1992 a,b). Like the neurotrophic polypeptides, valproic acid also shows very limited transfer into the central nervous system of the human (Lxc3x6scher et al., Epilepsia (1988) 29:311-316). For reviews of clinical and experimental valproic acid teratogenesis. cf. Nau et al., Pharmacol. Toxicol. (1991) 69:310-321; Nau, CIBA Foundation Symposium 181, pp. 615-664; Marcel Dekker, 1993.
Studies in vitro have demonstrated valproate to potently inhibit the rate of neural derived cell proliferation at concentrations within its therapeutic plasma level (Regan, C., Brain Res. (1985) 347:394-398). This antiproliferative action of valproate is restricted to a defined point in the G1 phase of the cell cycle. Martin M. and Regan C., Brain Res. (1991) 554:223-228. In the presence of valproate, cells assume a differentiated phenotype as judged by morphology, increased cell-substratum adhesivity and decreased affinity for concanavalin A lectin coated surfaces (Martin et al., Toxic in Vitro (1988) 2:43-48; Martin et al., Brain Res. (1988) 459:131-137; Maguire and Regan, Int. J. Devl. Neurosci. (1991) 9:581-586; Regan, C., Brain Res. (1985) 347:394-398. These actions of valproate are likely to be restricted to cells of the developing neural tube as, in in vivo experimental models, valproate has been shown to increase the incidence of neural tube defects and sequester specifically into the neuroephithelium where it generates cellular disarray (Dencker et al., Teratology (1990) 41:699-706; Ehlers et al., Teratology (1992) 45:145-151; Ehlers et al., Teratology (1992) 46:117-130; Kao et al., Teratogen. Mutagen, Carcinogen. (1981) 1:367-382; Turner et al., Teratology (1990) 41:421-442.
Hyperthermia, which induces neural tube defects (Chernoff and Golden, Teratology (1988) 37:37-42; Edwards, Teratogen. Mutagen. Carcinogen. (1986) 6:563-582; Shiota, Am J. Med. Genet. (1982) 12:281-288; Finnell et al., Teratology (1986) 33:247-252), also arrests neural cells in the G1 phase of the cell cycle both in vivo and in vitro (martin et al. Brain Res. (1991) 554:223-228; Walsh and Morris, Teratology (1989) 40:583-592); and produces similar pro-differentiative effects to those observed with valproate (Martin and Regan, Brain Res. (1988) 459:131-137). Thus, a coincident anti-proliferative and pro-differentiative action may identify agents which are capable of inducing neural tube defects yet provide a basis for the development of compounds useful for treatment or prevention of neurodegenerative diseases.
The studies of the structure activity relationship of teratogenic valproate-related compounds suggest a strict structural requirement for high teratogenic potency. Nau, H. et al., Pharmacol. and Toxicol. (1991) 69:310-321. Studies of structure-activity relationships were possible as a result of previous work demonstrating that the parent drug moleculexe2x80x94at least in the case of valproic acidxe2x80x94and not metabolite(s) proved responsible for the teratogenic action (Nau, Fundam Appl Toxicol, (1986) 6:662-668. Molecules which are highly teratogenic were reported to require an alpha-hydrogen atom, a free carboxyl function, and branching on carbon atom 2 with two chains containing three carbons each for maximum teratogenic activity. (Nau and Lxc3x6scher, 1986, Nau and Scott, 1986). Substances which do not conform with these strict structural requirements are of very low or negligible teratogenic activity, but still often exhibit good anticonvulsant activity in several experimental models. These compounds may therefore be valuable anti-epileptic agents (Nau et al., Neurology (1984) 34:400-402; Lxc3x6scher and Nau, Neuropharmacol (1985) 24:427-435; Wegner and Nau, Neurology (1992) 42 (Supp. 5):17-24; Elmazar et al., J. Pharm. Sci. (1993) 82:1255-1258. Teratogenic activity also demonstrated stereoisomeric preferences suggesting a stereoselective interaction between the drugs and a specific structure within the embryo.
In the case of 4-en-VPA (2-n-propyl-4-pentenoic acid) (Hauck and Nau, Toxicol Lett (1989) 49:41-48) and 4-yn-VPA (2-n-propyl-4-pentynoic acid) (Hauck and Nau, Pharm. Res. (1992) 9:850-855) the S-enantiomers proved to be more potent teratogens than the corresponding R-enantiomers. This stereoselective teratogenicity was due to differing intrinsic teratogenic potencies of the enantiomers, and not due to differences in pharmacokinetics as both enantiomers of a given pair reached the target tissue to the same degree, but one was more potent than the other (Hauck et al., Toxicol. Lett (1992) 60:145-153). Other examples supported the pronounced stereoselectivity of the teratogenic, but not the anticonvulsant and sedative effect (Hauck et al., Life Sci. (1990) 46:513-518; Nau et al., Pharmacol. and Toxicol. (1991) 69:310-321. Carbon chains connected to carbon atom 2 of valproate which were shorter or longer than 3 carbons reduced teratogenic activity. Nau et al. Id. Valproate""s antimitotic activity has been suggested as being related to its teratogenic potential rather than as a potential therapeutic asset, as the non-teratogenic valpromide analogue is not antiproliferative (Regan et al., Toxic in Vitro (1991) 5:77-82). Teratogenic analogs of valproate have been synthesized to date for the purpose of producing more desirable antiepileptic agents having fewer or no side effects and have not been suggested as being useful in their own right for other therapeutic purposes.
Despite continued efforts to identify compounds useful for treating neurodegenerative and proliferative disorders there is still a great need for useful compounds of increased efficacy and potency.
This invention provides compounds, pharmaceutical compositions and methods useful for promoting neuronal function and inhibiting cell mitosis. Accordingly, this invention also provides methods of preventing and treating neurodegenerative and proliferative disorders.
The compounds of this invention have the general formula (I) 
wherein
R1 is xe2x80x94Cxe2x89xa1CH, xe2x80x94CHxe2x95x90CH2 or xe2x80x94CH2xe2x80x94CH3,
R2 is a saturated, unsaturated, branched or unbranched C1-C30 alkyl group which is optionally substituted with a C3-C9 aliphatic or aromatic cyclohydrocarbon or heterocyclic group.
M is a hydrogen or a metal atom. Formula I is not 2-n-propyl-4-pentynoic acid (4-yn-VPA) or 2-n-propyl-4-pentenoic acid (4-en-VPA) and when R1 is xe2x80x94CH2xe2x80x94CH3, R2 is C5 to C30.
This invention also provides a method of making the compounds of the invention.
This invention also provides pharmaceutical compositions useful for inhibiting cell mitosis and/or promoting neuronal function comprising effective amounts of the compounds suitable for use in the treatments of the invention with a pharmaceutical carrier suitable for administration to an individual
In addition, this invention relates to methods of promoting neuronal function and/or survival, and in particular to methods of treating individuals with neurodegenerative disorders. The compounds useful for treating neurodegenerative disorders include those of formula I as described above including 2-n-propyl-4-pentenoic acid and 2-n-propyl-4-pentynoic acid, as well as those of formula II 
wherein R3 and R4 are independently of one another C1-C30 saturated or unsaturated, branched and/or unbranched aliphatic hydrocarbon, optionally substituted by a C3-9 aliphatic or aromatic cyclohydrocarbon, or heterocyclic group. M is hydrogen or a metal atom.
The compounds and compositions of this invention which are neurotrophic may be used to promote the survival and function of neurons which would otherwise have diminished function, degenerate or die. Accordingly, in addition to treating individuals diagnosed with a neurodegenerative disorder, the compounds and compositions of this invention may also be used prophylactically to prevent or retard the onset of neurodegenerative disorders in individuals identified as being at risk for developing such disorders.
In another embodiment of this invention, the compounds and compositions useful for treating neurodegenerative disorders may also be used to treat proliferative disorders. The antiproliferative activity of the compounds and compositions may be used to prevent or retard the formation of a wide variety of tumors by administering the compounds and compositions to a person in need of treatment. This treatment is especially useful for treating tumors of neuronal or glial origin given that these compounds penetrate the CNS.
It is an object of this invention to provide neurotrophic compounds useful for enhancing the survival of neurons and glial cells.
It is another object of this invention to provide compound and compositions useful for promoting the expression of characteristics associated with mature functioning neuronal or glial cells.
By promoting the survival and function of neuronal or glial cells, it is an object to this invention to provide compounds and compositions useful for the prevention and/or treatment of a variety of neurodegenerative disorders.
Another object of this invention is to provide compounds and compositions useful for inhibiting the pathologic proliferation of neuronal, glial or related cells.